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Original ArticleFree Preview

Restriction of Intravenous Fluid in ICU Patients with Septic Shock

List of authors.
  • Tine S. Meyhoff, M.D.,
  • Peter B. Hjortrup, M.D., Ph.D.,
  • Jørn Wetterslev, M.D., Ph.D.,
  • Praleene Sivapalan, M.D.,
  • Jon H. Laake, M.D., Ph.D.,
  • Maria Cronhjort, M.D., Ph.D.,
  • Stephan M. Jakob, M.D., Ph.D.,
  • Maurizio Cecconi, M.D.,
  • Marek Nalos, M.D., Ph.D.,
  • Marlies Ostermann, M.D., Ph.D.,
  • Manu Malbrain, M.D., Ph.D.,
  • Ville Pettilä, M.D., Ph.D.,
  • Morten H. Møller, M.D., Ph.D.,
  • Maj-Brit N. Kjær, R.N., M.Sc.,
  • Theis Lange, Ph.D.,
  • Christian Overgaard-Steensen, M.D., Ph.D.,
  • Björn A. Brand, M.D.,
  • Marie Winther-Olesen, M.D.,
  • Jonathan O. White, M.D.,
  • Lars Quist, M.D.,
  • Bo Westergaard, M.D.,
  • Andreas B. Jonsson, M.D.,
  • Carl J.S. Hjortsø, B.Sc.,
  • Nick Meier, B.Sc.,
  • Thomas S. Jensen, M.D.,
  • Janus Engstrøm, B.Sc.,
  • Lars Nebrich, M.D.,
  • Nina C. Andersen-Ranberg, M.D.,
  • Jacob V. Jensen, M.D.,
  • Neeliya A. Joseph, B.Sc.,
  • Lone M. Poulsen, M.D.,
  • Louise S. Herløv, B.S.N.,
  • Christoffer G. Sølling, M.D., Ph.D.,
  • Susan K. Pedersen, M.D.,
  • Kurt K. Knudsen, M.D.,
  • Therese S. Straarup, M.D.,
  • Marianne L. Vang, M.D.,
  • Helle Bundgaard, M.D.,
  • Bodil S. Rasmussen, M.D., Ph.D.,
  • Søren R. Aagaard, M.D., Ph.D.,
  • Thomas Hildebrandt, M.D.,
  • Lene Russell, M.D., Ph.D.,
  • Morten H. Bestle, M.D., Ph.D.,
  • Martin Schønemann-Lund, M.D.,
  • Anne C. Brøchner, M.D., Ph.D.,
  • Claes F. Elvander, M.D.,
  • Søren K.L. Hoffmann, M.D., Ph.D.,
  • Michael L. Rasmussen, M.D.,
  • Yvonne K. Martin, M.D.,
  • Fredrik F. Friberg, M.D.,
  • Herman Seter, M.D.,
  • Tayyba N. Aslam, M.D.,
  • Sigrid Ådnøy, M.D.,
  • Philipp Seidel, M.D.,
  • Kristian Strand, M.D., Ph.D.,
  • Bror Johnstad, M.D.,
  • Eva Joelsson-Alm, R.N., Ph.D.,
  • Jens Christensen, M.D.,
  • Christian Ahlstedt, M.D.,
  • Carmen A. Pfortmueller, M.D., Ph.D.,
  • Martin Siegemund, M.D.,
  • Massimiliano Greco, M.D.,
  • Jaroslav Raděj, M.D.,
  • Miroslav Kříž, M.D.,
  • Doug W. Gould, Ph.D.,
  • Kathy M. Rowan, Ph.D.,
  • Paul R. Mouncey, M.Sc.,
  • and Anders Perner, M.D., Ph.D.
  • for the CLASSIC Trial Group*



Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU).


Download a PDF of the Research Summary.

In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization.


We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], −4.7 to 4.9; P=0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, −1.7 percentage points; 99% CI, −7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups.


Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC number, NCT03668236.)

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IV Fluid Restriction in Septic Shock

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Funding and Disclosures

Supported by a grant (NNF17OC0028608) from the Novo Nordisk Foundation and by the Sofus Friis’ Foundation, the Rigshospitalets Research Council, and the Danish Society of Anesthesiology and Intensive Care Medicine.

Disclosure forms provided by the authors are available with the full text of this article at

This article was published on June 17, 2022, at

A data sharing statement provided by the authors is available with the full text of this article at

Author Affiliations

From Copenhagen University Hospital–Rigshospitalet (T.S.M., P.B.H., P. Sivapalan, M.H.M., M-B.N.K., C.O.-S., B.A.B., M.W.-O., J.O.W., L.Q., B.W., A.B.J., C.J.S.H., N.M., T.S.J., A.P.), the Copenhagen Trial Unit, Center for Clinical Intervention Research (J.W., J.E.), the Section of Biostatistics, University of Copenhagen (T.L.), Copenhagen University Hospital–Bispebjerg and Frederiksberg (S.K.L.H.), Copenhagen, Zealand University Hospital, Køge (L.N., N.C.A.-R., J.V.J., N.A.J., L.M.P., L.S.H.), Viborg Hospital, Viborg (C.G.S., S.K.P., K.K.K., T.S.S.), Randers Hospital, Randers (M.L.V., H.B.), Aalborg University Hospital, Aalborg University, Aalborg (B.S.R., S.R.A.), Zealand University Hospital, Roskilde (T.H., L.R.), Copenhagen University Hospital–North Zealand, Hillerød (M.H.B., M.S.-L.), Kolding Hospital, University of Southern Denmark, Kolding (A.C.B., C.F.E.), and Herning Hospital, Herning (M.L.R.) — all in Denmark; Oslo University Hospital, Oslo (J.H.L., T.N.A., S.Å.), Hospital Østfold Kalnes, Grålum (Y.K.M., F.F.F., H.S.), Stavanger University Hospital, Stavanger (P. Seidel, K.S.), and Hospital Innland Hamar, Hamar (B.J.) — all in Norway; Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset (M. Cronhjort, E.J.-A., J.C.), and Karolinska University Hospital, Huddinge (C.A.) — both in Sweden; Inselspital, Bern University Hospital, University of Bern, Bern (S.M.J., C.A.P.), and Basel University Hospital, Basel (M.S.) — both in Switzerland; IRCCS Humanitas Research Hospital, Humanitas University, Milan (M. Cecconi, M.G.); University Hospital Pilsen, Pilsen, Czech Republic (M.N., J.R., M.K.); Guy’s and St. Thomas’ Hospital (M.O.) and the Clinical Trials Unit, Intensive Care National Audit and Research Centre (D.W.G., K.M.R., P.R.M.) — both in London; University Hospital Brussels, Brussels (M.M.); and the University of Helsinki and Helsinki University Hospital, Helsinki (V.P.).

Dr. Perner can be contacted at or at the Department of Intensive Care, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

A complete list of investigators in the Conservative versus Liberal Approach to Fluid Therapy in Septic Shock (CLASSIC) Trial Group is provided in the Supplementary Appendix, available at